Discovery of Polymyxin-based Antibacterial Agents Active Against Multi-Drug Resis

描述(申请人提供)：多重耐药病原菌的出现对人类生命和国家医疗保健系统构成了严重且日益严重的威胁。现在，每年有10万S死于这些超级细菌，据估计，这些超级细菌在美国增加了200亿美元的医疗费用。特别是，肺炎克雷伯氏菌、大肠杆菌、鲍曼不动杆菌和铜绿假单胞菌等革兰氏阴性菌株的扩张以及迅速传播的NDM-1表型令人严重关切。对于许多革兰氏阴性感染，粘菌素(多粘菌素E)仍然是唯一的“最后手段”，在那里碳青霉烯类抗生素不再起作用，而且已经有报告说有替格环素耐药病例。目的和目的：我们的目标是生产以粘菌素为基础的新抗生素，这种抗生素对耐药的超级细菌有效，并且比目前的“最后抵抗”抗生素具有更好的安全性。这项研究将提供针对耐药病原菌的新候选药物，还将提供对抗生素引起的肾毒性(肾毒性)的来源和机制的详细科学理解。我们将对粘菌素如何杀灭细菌有详细的了解。从长远来看，为分析肾毒性而开发的分析方法将在药物研究的所有领域证明是有价值的，从而为抗生素-肾毒性和更一般的药物-肾毒性筛选提供工具。新的粘菌素衍生物将有效地对抗严重的革兰氏阴性超级细菌，并攻击药物敏感和耐药的细菌菌株。方法与方法：本项目将使用世界上第一个快速合成1,400个粘菌素类似物的合成方法，进行前所未有的结构-活性和结构-毒性关系的系统研究。这些新化合物将优化对耐药革兰氏阴性细菌，特别是NDM-1菌株的活性，然后评估作用模式、稳定性、细胞毒性和肾毒性。它们还将被配置为与细菌膜和分子靶标(Lipid A)结合。这将导致药物作用的体内原则证明和药物动力学研究，以选择化合物进行未来的临床前评估。

DESCRIPTION (provided by applicant): The emergence of multi-drug resistant pathogenic bacteria represents a serious and growing threat to human lives and national healthcare systems. These 'supebugs' now kill 100,000's of people each year and are estimated to add $20bn in healthcare costs in the US. In particular, the expansion of Gram-negative strains such as Klebsiella pneumonia, Escherichia coli, Acinetobacter baumannii and Pseudomonas aeruginosa and the rapidly spreading NDM-1 phenotypes are of grave concern. For many of these Gram-negative infections, colistin (polymyxin E) remains the only option of 'last resort', where the carbapenems are no longer active, and cases of tigecycline resistance have been reported. Aims & Objectives: We aim to produce new antibiotics, based on colistin, that are active against resistant 'super-bugs' and that have better safety profiles than current 'last-resor' antibiotics. The research will deliver novel drug-candidates targeted at resistant pathogenic bacteria, and will also provide a detailed scientific understanding of the origins and mechanisms of antibiotic-induced kidney toxicity (nephrotoxicity).We will develop a detailed understanding of how colistin works to kill bacteria. In the longer term, the assays developed for profiling of nephrotoxicity will prove valuable in all areas of drug research, thus providing tools for both antibiotic-renal and more general drug-renal toxicity screening. The new colistin derivatives will be active against the serious Gram-negative super superbugs and attack both drug-sensitive and drug-resistant strains of the bacteria. Approach & methods: This program will use a world first synthetic method for the rapid synthesis of 1,400 colistin analogs for an unprecedented systematic investigation of structure-activity and structure- toxicity relationships. These novel compounds will be optimized for activity against drug-resistant Gram-negative bacteria, in particular NDM-1 strains, and then evaluated for mode of action, stability, cell toxicity and nephrotoxicity. They will also be profiled for binding to the bacterial membranes and molecular target (Lipid A). This will lead to in vivo proof-of-principle for drug action and pharmacokinetic studies for the selection of compounds for future pre-clinical evaluation.